Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript, purported to be a review, is not a review, as it is a compilation of figures and key findings from other publications, as well as multiple repetitions of several points included in various sections. The manuscript does not contain any scientific novelty or structuring of concepts regarding the intestinal microbiome. The mention of several bacterial taxa, named without adjustment to modern taxonomy, does not constitute a description of the microbiome.

Author Response

We sincerely thanks Reviewer for taking the time to evaluate our manuscript and for providing constructive feedback. We highly value the reviewer’s perspective, which has guided us to refine the scientific presentation and structure of our review.
Below, we have addressed each point raised in detail.

Comment 1: The manuscript, purported to be a review, is not a review, as it is a compilation of figures and key findings from other publications, as well as multiple repetitions of several points included in various sections. The manuscript does not contain any scientific novelty or structuring of concepts regarding the intestinal microbiome. The mention of several bacterial taxa, named without adjustment to modern taxonomy, does not constitute a description of the microbiome.

Comment 1.1: The manuscript contains multiple repetitions of several points included in various sections.

Response 1.1: We acknowledge this important comment. However, the reviewer did not specify the exact locations of repetition points. Therefore, we performed a comprehensive review of the entire manuscript to remove redundancy and ensure non-repetitive content flow. after review and other Reviewer comment "who had mentioned about repeated sentences (as e.g., the duplicated statement on Page 17 regarding bacterial species and tumor growth). So we have revised our manuscript accordingly and revised by removed similar paragraph and write about related to the section in line no. 640. And as well as we have found some 4-5 references which was repeated 2 times,  we removed them.

If Reviewer have noticed any other duplicated statement or sentences we are open to revised our manuscript.

These revisions have substantially improved readability, clarity, and coherence.

 

Comment 1.2: The manuscript does not contain any scientific novelty or structuring of concepts regarding the intestinal microbiome.

Response 1.2: To address the concern regarding structural and conceptual organization, we implemented a major structural revision of the manuscript. The content has been reorganized into a clear, thematic, and logical flow that progresses. The new name of main heading which we have revised is as follows along with major shifting of contents:

Heading which is modified: 

2. Composition and Functional Diversity of the Gut Microbiota (Composition and Function of the Gut Microbiota) (Line no. 130) and we have done some changes in content shifting like sub section 2.2.5. Gut Barrier Integrity move to section as 3.3. Gut Barrier Integrity in line no. 293, as well as we have shifted the table 1 from section 2.4 to the sub section 4.1.1. (line no. 372)

3. Microbiota–Immune and Metabolic Interactions The Gut Microbiome and Host Systems (Line no. 251)

5. Microbiota-Derived Metabolites and Therapeutic Implications (Therapeutic Interventions Targeting the Gut Microbiota) (Line no. 528)

8. Personalized and Translational Approaches (Emerging Trends and Future Perspectives) (Line no. 778)

9. Limitations and Future Directions section added (line no. 863)

This reorganization and Headings which is updated may ensures that the manuscript is not merely a compilation of published findings but a concept-driven synthesis that highlights key mechanisms, interconnections, and translational relevance.

These improvements collectively establish a clear conceptual structure and enhance the manuscript’s scientific contribution.

 

Comment 1.3: Bacterial taxa mentioned in the text are not updated to modern taxonomy.

Response 1.3: We fully acknowledge this and have carefully reviewed bacterial nomenclature and adjusted to modern taxonomy to ensure consistency with the latest LPSN (List of Prokaryotic names with Standing in Nomenclature) and NCBI Taxonomy Database classifications. And also we have revised in manuscript at the end of Introduction section about this information (line no. 125-129).

Changes made:

• Updated outdated genera and species names through out the manuscript specially we have Revised the related sections and tables accordingly to reflect accurate taxonomic updates. (e.g., Lactobacillus casei → Lacticaseibacillus casei; Lactobacillus plantarum → Lactiplantibacillus plantarum).

This ensures that all microbial references conform to current scientific standards.

Concluding Statement:

These improvements have enhanced the depth, conciseness, and scientific precision of the paper, ensuring it now provides a comprehensive, updated, and well-structured overview of the gut microbiota’s immune-metabolic role and clinical potential.

We hope that the revised version meets the reviewers’ expectations and is now suitable for publication.

Reviewer 2 Report

Comments and Suggestions for Authors

In this review manuscript, the authors discuss the crucial roles of the gut microbiota in modulating human health, including its influence on immune system development, neuropsychiatric disorders, the tumor microenvironment, inflammatory bowel disease, and metabolic disorders—extending beyond its traditional role in digestion. The review also emphasizes the importance of gut microbiota-derived metabolites in disease pathogenesis and highlights therapeutic strategies targeting the microbiota—such as prebiotics, probiotics, synbiotics, fecal microbiota transplantation and dietary modfication—for maintaining health and treating various diseases. The authors referenced an extensive body of literature and extracted key insights relevant to the topic. In conclusion, this is a solid and valuable review article. However, several concerns need to be addressed.

The manuscript appears overly lengthy, with numerous instances of repetitive sentences across different paragraphs—even within the same page. For example, in page 17, the sentence “Research indicates that specific bacterial species and their metabolites can either promote or inhibit tumor growth, and also modulate the efficacy of cancer treatments (Desai et al., 2025).” was presented twice. The authors are advised to revise the manuscript for conciseness.

 

In Table 1, butyrate is a short chain fatty acid, which should be included in the row ”SCFAs & metabolites”

In the abstract, the order “ metagenomics, metabolomics, transcriptomics, and proteomics” need be changed.

 

Some references seem missing. For example, in page 7, a reference should be cited in the sentence “In contrast, disruption of this delicate balance—known as dysbiosis—has been strongly linked to the onset and progression of a wide range of disorders, including obesity, diabetes, inflammatory bowel disease, neurodegenerative conditions, and even certain cancers.”

 

Author Response

We sincerely thanks to the reviewer for the constructive and valuable feedback. We have carefully revised the manuscript to improve its novelty, conceptual clarity, structure, and conciseness. Below is a detailed response to each comment:

Comment 1: The manuscript appears overly lengthy, with numerous instances of repetitive sentences across different paragraphs—even within the same page. For example, in page 17, the sentence “Research indicates that specific bacterial species and their metabolites can either promote or inhibit tumor growth, and also modulate the efficacy of cancer treatments (Desai et al., 2025).” was presented twice. The authors are advised to revise the manuscript for conciseness.

Response 1: We appreciate this valuable observation. The manuscript has been carefully revised for conciseness. The Repetitive sentences have been removed, particularly from the section 6. Gut Microbiota in Cancer and Immunotherapy” (Line no. 641-646) Repetitive statements in the form of the whole paragraph and we have placed missing details, and as well as we have review our manuscript so we  did not find any other repetitive sentences or paragraph except references, so we removed 4-5 References which was also repeated in reference list.

And about the manuscript length, we need guidance to revised our manuscript, But did not find any suggestion or instruction from reviewer other than example, in page 17. So without any other instruction we tried out best to find other repetitive sentences which may help us to reduce lengthy of our Manuscript. We are open for any other revision suggested by Reviewers.

Comment 2: In Table 1, butyrate is a short chain fatty acid, which should be included in the row ”SCFAs & metabolites”.

Response 2 : Thank you for highlighting this correction. Table 1 (Line no. 372) has been revised, and butyrate is now correctly listed under the “SCFAs & metabolites” row, along with acetate and propionate, whole row is updated accordingly.

Comment 3 : In the abstract, the order “ metagenomics, metabolomics, transcriptomics, and proteomics” need be changed.

Response 3 : The omics order has been corrected for logical flow. The revised phrase now mentioned in line no. as: “metagenomics, transcriptomics, proteomics, and metabolomics” in line no. 29-30.

Comment 4: Some references seem missing. For example, in page 7, a reference should be cited in the sentence “In contrast, disruption of this delicate balance—known as dysbiosis—has been strongly linked to the onset and progression of a wide range of disorders, including obesity, diabetes, inflammatory bowel disease, neurodegenerative conditions, and even certain cancers.”

Response 4 : We appreciate this valuable observation. The manuscript has been carefully revised by adding missing references. The revised sentence and corresponding references are now included as:

"In contrast, disruption of this delicate balance—known as dysbiosis—has been strongly linked to the onset and progression of a wide range of disorders, including obesity, diabetes, inflammatory bowel disease, neurodegenerative conditions, and even certain cancers (Gilbert et al., 2025; Arnold et al., 2018)." in line no. 219.

Reviewer 3 Report

Comments and Suggestions for Authors

Although this manuscript is well planned, written, and grammatically sound, I do have the following suggestions to improve the quality of the manuscript. 

A. Please add a few more recent references to the "Personalized Microbiome-Based Therapies",  "Ethical and Regulatory Challenges in Microbiome Research", "Long-Term Implications of Gut Microbiota Modulation" sections.

B. Please add a few references and studies based on cardiovascular diseases, psoriasis, and skin disorders, Neurological Disorders, Cancer and immunotherapy, etc.

C. Please include the limitations of the microbiome study in various diseases. 

D. Please include the recent methods and technologies, such as multi-omics, machine learning, and metagenomics, used in microbiomes to identify the roles of microbes in various diseases. 

 

Author Response

We sincerely thanks the reviewers for constructive and valuable feedback. We have carefully revised the manuscript to improve its novelty, conceptual clarity, structure, and conciseness. Below is a detailed response to each comment:

Comment A: Please add a few more recent references to the "Personalized Microbiome-Based Therapies",  "Ethical and Regulatory Challenges in Microbiome Research", "Long-Term Implications of Gut Microbiota Modulation" sections.

Response A: We have enriched these sections with the latest literature (2022–2025) and expanded their content to reflect current developments.

• Changes made:

  • between Page no. 22 , Line no. 822-826: Added discussion on personalized microbiome-based therapy, AI-guided interventions, and FMT responder profiling.

New References: (Ayesiga et al., 2024), (Kashyap et al., 2017).

• • Page no. 22, Line no. 838: Expanded reference by including in-text citation from recently published article in "Ethical and Regulatory Challenges in Microbiome Research" Sub section.

New References: (Rodriguez et al., 2024),  (Ejtahed et al., 2023).

• • Page no. 23, Lines 853: Expanded reference in  "Long-Term Implications of Gut Microbiota Modulation" sections by including in-text citation from recently published article.

New References:  (Desai et al., 2025), (Jaswal et al., 2025).  

 

Comment B:   Please add a few references and studies based on cardiovascular diseases, psoriasis, and skin disorders, Neurological Disorders, Cancer and immunotherapy, etc.

Response B: We appreciate this recommendation and have integrated additional studies and references along with in-text citation for covering these diseases.

• Changes made:

  • Cardiovascular Diseases: Page no. 20, Line no. 712-719 – Added discussion on microbial TMAO production and atherosclerosis.

New References: (Muttiah & Hanafiah, 2025), (Mak & Shekhar, 2025), and (David & Lev-Ari, 2024).

• • Neurological Disorders: Page no. 20, Line no. 733–739. Added microbiota–brain axis mechanisms and neurotransmitter regulation.

New References:  (Jagodic et al., 2025), and (Giau et al., 2018).

• • Psoriasis and Skin Disorders: Page no. 21 , Line no.  754-757. Expanded description of SCFA-producing bacteria and Th17 cell modulation.

 New References: (Yoshida et al., 2023) and (Fallahi et al., 2025). 

• • Cancer and Immunotherapy: Page no. 17, Line no. 641-648. Added recent findings on Akkermansia muciniphila and Bifidobacterium longum enhancing immune checkpoint inhibitor (ICI) responses.

 New References: (Simpson et al., 2023), (Lin et al., 2025).

Comment C: “Please include the limitations of microbiome studies in various diseases.”

Response C: We have added a new Section titled ‘9. Limitations and Future Directions’ between the line no. 863-878. Just before the Conclusion to address current challenges such as inter-individual variability, lack of standardization, and short study durations.

• • New reference:  (Wilson et al., 2025).

Comment D: Please include the recent methods and technologies, such as multi-omics, machine learning, and metagenomics, used in microbiomes to identify the roles of microbes in various diseases. 

Response D: We have expanded Section 8. Personalized and Translational Approaches (Emerging Trends and Future Perspectives) in line no. 778 by adding Sub section 8.1 Recent Methods & Technologies to incorporate recent technological advances in multi-omics integration, AI-based modeling, and single-cell approaches.

• Changes made:

  • Page no.  21, Line no. 786: Added paragraph describing shotgun metagenomics, spatial transcriptomics, and machine learning-based predictive modeling.

References added: (O'Sullivan et al., 2025), and  (Northen et al., 2025).